1. Field of the Invention
This invention relates generally to new immunomodulatory peptides and particularly to conformationally restricted compounds similar to the peptide thymopentin.
2. Description of the Art
U.S. Pat. Nos. 4,190,646 and 4,261,886 disclose various pentapeptides having activity similar to the long chain polypeptide known as thymopoietin, which is described in U.S. Pat. Nos. 4,002,740 and 4,077,949. Thymopoietin selectively stimulates the differentiation of T cells. The pentapeptide disclosed in the '646 patent, which has the sequence H-ARG-LYS-ASP-VAL-TYR-OH, is known as the thymopoietin pentapeptide or "thymopentin". The biological activity of certain of these peptides is described in an article by M. E. Weksler, et al., J. Exp. Med. 148: 996-1006 (1978). The above United States patents and article are incorporated herein by reference. U.S. Pat. Nos. 4,361,673 and 4,420,424 also disclose various peptides asserted to have activity similar to thymopoietin. These disclosed peptides are all linear.
The functional relationship between linear peptides and their cyclic forms is not well understood and is certainly not in any way predictable. For example, the linear octapeptide angiotensin II exhibits high pressor activity while the corresponding cyclic octapeptide exhibits little such activity. Other examples are known.
Based upon the proton nmr studies of thymopoietin in solution it is also unexpected that the cyclic peptides of this invention have thymopoietin-like activity. See, for example, N.R. Krishna, et al., Biochemistry, 19, 5557 (1980).
Certain enzyme-resistant immunomodulatory peptides are disclosed in copending application Serial No. 553,281, filed Nov. 18, 1983, which is incorporated herein by reference.
Thymopentin has been shown to exert a modulatory effect on the immune system of animals and humans and is thus useful for treatment of diseases involving defects in immune function, whether such defects are manifested as deficiencies or excesses of immune function. See for example Audhya, T. and Goldstein, G., Int. J. Pept. Protein Res., 22, 568-572 (1983); Aiuti, et al., Lancet 1:551-555 (1983); and Levinsky, et al., in "Primary Immunodeficiency Diseases", Wedgewood, Rosen, and Paul, eds, 19, 273-276 (1983). Reference is made to these articles and to the above-described patents and article for a discussion of other background material and the biological processes involved in the present invention.
The present invention provides conformationally restricted cyclic peptides and peptide compositions which surprisingly possess thymopentin-like activity and thus offer significant advantages in the treatment of immune defects.